The sources and characteristics of calcium signals determine whether autophagy is up- or downregulated.

Chehab, Tala; Rietdorf, Katja; Parys, Jan B.; Bultynck, Geert and Bootman, Martin D. (2016). The sources and characteristics of calcium signals determine whether autophagy is up- or downregulated. In: 14th International Meeting of the European Calcium Society, 25-29 Sep 2016, Valladolid, Spain.

Abstract

Autophagy is a catabolic process important for cell survival and homeostasis that involves degradation of dysfunctional cellular components. Disruption of autophagy is associated with many disorders. Calcium has been proposed to be both pro- and antiautophagic. To understand how calcium can have these opposing effects, we investigated how particular sources of calcium, and the characteristics of calcium signals, impact on autophagy. It has been proposed that calcium transfer from InsP3Rs to the mitochondrial matrix stimulates ATP production, and thereby prevents the induction of autophagy. Consistent with this hypothesis, we found that inhibiting calcium release from InsP3Rs, or inhibiting mitochondrial respiration, stimulated autophagy in HEK and HeLa cells. These data suggest that the absence of cellular calcium signals is pro-autophagic. However, evoking cytosolic calcium signals by inhibiting SERCA with cyclopiazonic acid (CPA) also stimulated autophagy in the presence of extracellular calcium, suggesting that a sustained calcium influx signal was needed. Inhibition of calcium/calmodulin-dependent kinase kinase (CaM-KK) prevented CPA-induced autophagy, suggesting that cytosolic calcium elevation induces autophagy via CaM-KK-mediated phosphorylation. Finally, we find that BAPTA inhibited autophagy evoked by either InsP3R inhibition, CPA, rapamycin or nutrient starvation, again highlighting the importance of calcium signals in autophagy induction. The results illustrate the dual effect of calcium on autophagy; both the absence of calcium signals (following InsP3R inhibition) and the presence of calcium signals (following SERCA inhibition) stimulate autophagic flux. Clamping calcium signals with BAPTA inhibits autophagy induction by all treatments used, consistent with a calcium-dependent step in the initiation of autophagosome formation.

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